The effect of tricyclic antidepressants on cerebral fluid dynamics

Tricyclic antidepressants are thought to act primarily via effects on adrenergic neurotransmitters. Recent research supports the concept that a major function of the central adrenergic system is the modulation of cerebral fluid dynamics. Based on this concept, studies in the rat were conducted to assess the effects of these drugs on cerebral capillary permeability and flow by quantitating changes in the extraction fraction of water (E(w)). Amitriptyline and nortriptyline produced significant increases in E(w) for the total forebrain (from control values of 0.67 to experimental values as high as 0.99) while protriptyline had no effect on E(w). The amitriptyline-induced increase in E(w) occurred at doses which produced plasma levels (500 ng/ml) near the range defined as therapeutic in depression studies. The magnitude of the effect was similar for both amitriptyline and nortriptyline representing a 35-40% increase over control values. The effects were uniformly observed throughout the forebrain: rostral telencephalon, caudal telencephalon, and diencephalon.